A number of dihydropteridione derivatives are already known in the prior art. Thus, for example, International Patent Applications WO 03/020722 and WO 2004/076454 disclose dihydropteridione derivatives, a process for their manufacture and their use in a pharmaceutical composition to treat diseases connected with the activity of specific cell cycle kinases and characterised by excessive or abnormal cell proliferation.
The compound N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide and a process for its manufacturing are specifically disclosed in WO 2004/076454.
However, the above-mentioned patent applications do not disclose any specific crystal form of any of the compounds exemplified therein.
Although the pharmacologically valuable properties of the dihydropteridinone derivatives disclosed in the art and mentioned above constitute the basic prerequisite for effective use of the compounds as pharmaceutical compositions, an active substance must in any case satisfy additional requirements in order to be accepted for use as a drug. These parameters are largely connected with the physicochemical nature of the active substance. Hence, there continues to be a need for novel crystalline forms of active substances, which can be conveniently formulated for administration to patients and which are pure and highly crystalline in order to fulfil exacting pharmaceutical requirements and specifications.
Preferably, such compounds will be readily formed and have favourable bulk characteristics. Examples of favourable bulk characteristics are drying times, filterability, solubility, intrinsic dissolution rate, stability in general and especially thermal stability, and hygroscopicity.
An absence of breakdown products in the pharmaceutical composition being used is also favourable, since if breakdown products are present in the pharmaceutical composition the content of active substance present in the pharmaceutical formulation might be lower than specified.
Another critical parameter to be controlled is the hygroscopicity, since the absorption of moisture reduces the content of pharmaceutically active substance as a result of the increased weight caused by the uptake of water. Pharmaceutical compositions with a tendency to absorb moisture have to be protected from moisture during storage, e.g. by the addition of suitable drying agents or by storing the drug in an environment where it is protected from moisture. In addition, the uptake of moisture may reduce the content of pharmaceutically active substance during manufacture if the pharmaceutical substance is exposed to the environment without being protected from moisture in any way. Preferably, therefore, the hygroscopicity of a pharmaceutically active substance should be well characterised, and possibly also stabilized.
As the crystal modification of an active substance is important to the reproducible active substance content of a preparation, there is a need to clarify as far as possible any existing polymorphism of an active substance present in crystalline form. If there are different polymorphic modifications of an active substance care must be taken to ensure that the crystalline modification of the substance does not change in the pharmaceutical preparation later produced from it. Otherwise, this could have a harmful effect on the reproducible potency of the drug. Against this background, active substances characterised by only slight polymorphism are preferred.
Another criterion which may be of exceptional importance under certain circumstances depending on the choice of formulation or the choice of manufacturing process is the solubility and dissolution behaviour of the active substance. If for example pharmaceutical solutions are prepared (e.g. for infusions) it is essential that the active substance should be sufficiently soluble in physiologically acceptable solvents, particularly aqueous media. For drugs which are to be taken orally, it is in general very important that the active substance should be sufficiently soluble, readily dissolvable and bioavailable.
Decreased levels of organic solvents in the crystal lattice are also favourable, due in part to potential solvent toxicity to the recipient as a function of the solvent.
Under certain circumstances, it may be also favourable for drug development to use an anhydrous form than a hydrate form, since, for example, preparation and handling of hydrates might be sometimes difficult as reproducibility and stability of the hydrated forms may depend on external influences in complex manner, or some hydrates might tend to be less soluble with respect to homologous anhydrous forms, with potential detrimental effect also on the dissolution rate properties of the active compound per se and on its absorption profile through the gastrointestinal tract.
Furthermore, the process for preparing such a compound also needs to be conveniently carried out on commercial scale.
Hence, without being restrictive, examples of the parameters which needs to be controlled are the stability of the starting substance under various environmental conditions, the stability during production of the pharmaceutical formulation and the stability in the final compositions of the drug.
The pharmaceutically active substance used to prepare the pharmaceutical compositions should therefore have great stability which is ensured even under all kinds of environmental conditions.
Moreover, as it may be of further advantage for acceptance for use as a drug, it may be favourable that the active substance is suitable for oral administration. Likewise, it may be favourable that the active substance is useful for the manufacture of solid oral pharmaceutical forms, such as tablets and capsules, or liquid oral pharmaceutical forms, such as orally administered solutions and suspensions, whereby emphasis might be given to solid oral dosage forms.
The problem of the present invention is thus to provide a pharmaceutically active substance which is not only characterised by high pharmacological potency but also satisfies the above-mentioned physicochemical requirements as far as possible.